Biomedical subjects

R Matasić

Publications and source records attributed to R Matasić.

3 recordsLinked to original sources

PubMed2001

Maturation of human dendritic cells as sulfasalazine target.

AIM: Sulfasalazine, a nonsteroidal anti-inflammatory drug, is effective in treating some autoimmune diseases, but its mechanism of action is unclear. To determine whether dendritic cells could be a possible target of the drug, we studied the effects of sulfasalazine and its metabolites, aminosalicylate and sulfapyridine, on in vitro maturation (terminal differentiation) of human myeloid dendritic cells. METHODS: We prepared immature dendritic cells by incubating CD14-positive cells in the presence of granulocyte- macrophage colony-stimulating factor and interleukin (IL)-4. The cells were matured by addition of tumor necrosis factor (TNF)-a, IL-1 beta, and prostaglandin E2 in the presence of sulfasalazine or its metabolites -- aminosalicylate and sulfapyridine, or their combinations. We quantified the effect of drugs on the dendritic cell characteristics, such as stimulation of autologous and allogeneic pan-T cell proliferation, surface marker phenotype, IL-12 p40 subunit secretion, and activation of nuclear transcription factor (NF)-kappa B. RESULTS: Dendritic cells treated with sulfasalazine (1.25 micromol/L or 2.5 micromol/L) could not stimulate T cells (p<0.028, two-sided paired t-test). In distinction to drug-free maturing dendritic cells, 2.5 micromol/L sulfasalazine upregulated the levels of CD14 and CD68 and downregulated the levels of CD40, CD80, and CD83 (for all CD markers, p<0.03 for difference between measurements in the absence and the presence of sulfasalazine). From concentration-dependent changes in CD83 expression, we found an apparent ID50 >>1.5 micromol/L sulfasalazine. The apparent ID50 value for aminosalicylate-inhibited maturation was 4 micromol/L. Sulfapyridine had no effect. At 1.25 micromol/L, sulfasalazine largely inhibited NF-kB activation in dendritic cells. CONCLUSION: Maturing human dendritic cells are hundred-fold more sensitive to sulfasalazine than T cells and NK cells and the most sensitive human cells described so far. Thus, dendritic cell maturation is an important target of sulfasalazine. Because of the role of dendritic cells in (auto)immunity, inhibition of their maturation might provide a target for further optimization of sulfasalazine therapy.

Anti-Inflammatory Agents, Non-Steroidal↗

PubMed2000

Maturation of human monocyte-derived dendritic cells studied by microarray hybridization.

We compared the transcript profiles of human myeloid immature dendritic (IDC) cells and mature dendritic cells (MDC) by hybridization of cell-derived cDNA to DNA probes immobilized on microarrays. The microarrays contained probes for 4110 known genes. We report maturation-dependent changes in transcription of clusters of differentiation, cytokines, cytokine receptors, chemokines, chemokine receptors, neuropeptides, adhesion molecules, and other genes. We identified 1124 transcripts expressed in IDC and 1556 transcripts expressed in MDC. Maturation increased the levels of 291 transcripts twofold or more and reduced the levels of 78 transcripts to one-half or less than in IDC. We identified a concerted maturation-stage-dependent transcription of the variable chains of the members of the gamma-chain-cytokine receptor family IL-4R, IL-7R, and IL-15R. Also, we found the reversal of the ratio of transcripts for galectin-3 and galectin-9 upon maturation. We identified maturation-dependent changes in the levels of transcripts for numerous genes encoding proteins previously undetected in dendritic cells such as indoleamine 2,3-deoxygenase, Epstein-Barr virus induced protein 3 and kinesin-2. Moreover, MDC transcribed and translated insulin like growth factor-1 receptor, transforming growth factor alpha, and neuropeptide Y.

Antigens, CD↗

PubMed1999

Dexamethasone inhibits dendritic cell maturation by redirecting differentiation of a subset of cells.

To investigate how corticosteroids affect differentiation of human dendritic cells (DC) in a defined inflammatory environment, we incubated immature DC with dexamethasone in the presence of tumor necrosis factor alpha (TNF-alpha), interleukin-1beta (IL-1beta), and prostaglandin E2. Dexamethasone inhibited differentiation into mature DC, as indicated by the reduced expression of antigen-presenting molecules, costimulatory and adhesion molecules, a marker of mature DC, and IL-12. Dexamethasone increased expression of CD14, CD36, and CD68, molecules characteristic of monocytes/macrophages and induced CD14+CD83- cells, a subset distinct both from immature DC and mature DC. The effects were concentration-dependent, with ID50 values between 2 and 30 nM dexamethasone. Unlike T and B cells, in DC dexamethasone induced no apoptosis, although it suppressed activated nuclear transcription factor NF-kappaB. Dexamethasone reduced the ability of DC to stimulate proliferation of allogeneic T cells in proportion to the level of CD14+CD83- cells in the population. CD83+ cells, isolated from dexamethasone-treated populations, retained the synthesis of IL-12 and the ability to stimulate proliferation of allogeneic T cells. Our data demonstrate that the dominant effect of the drug was redirecting differentiation of a subset of cells despite the presence of inflammatory cytokines. The observed ID50 values indicate that inhibition of DC differentiation might contribute significantly to in vivo immunosuppression by chronic administration of corticosteroids.

Antigen Presentation↗